Characterizing liver pathology and innate immune activity in experimental models of simulated spaceflight, aging, and circadian disruption

Abstract

Human exploration in space is challenged by the exposure to environmental hazards that pose a risk to survival and recovery. The extent of physiological threats goes beyond what is currently known. Mechanosensitive bone resorption in microgravity is well documented and now focus has shifted to understanding how morphological changes in bone affect the bone marrow niche. Investigating bone marrow derived immune cells and their interaction in peripheral tissues is at the leading edge of spaceflight and disease research. This work uses models of environmental stresses relevant to spaceflight to deepen the understanding necessary to enable sustained human exploration in space. A motivating factor is the observed accumulation of lipids in the liver and apparent metabolic disorder of animals flown on the International Space Station. Others have highlighted the similarity to Non-Alcoholic Fatty Liver Disease (NAFLD), a prevalent condition on Earth, where innate immune response is a factor in recovery from or progression of the disease. Here we aim to recapitulate the observed condition by using mechanical unloading, radiation exposure, circadian disruption, and aging as individual factors experienced in spaceflight to deepen understanding of the threats posed. We find these models initiate early signs of NAFLD, though focus falls to altered monocyte function as a core feature of environmental disruption. Mechanical unloading and radiation distinctly influenced transcriptional signals of liver resident macrophages partially dependent on infiltrating monocytes. In our investigation of circadian disruption and neurodegenerative disease, monocytes in the bone marrow demonstrated distinct transcriptional regulation biasing them toward activation and inflammatory response. Finally in our model of aging we explore the function of cell fate regulator Cdkn1a/p21 and how it may shape monocyte response. Together these investigations take a multi-faceted exploratory approach to uncover how environmental stimuli may shape metabolic and immune health in space with applications to all humans on Earth.